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Adams GP , McCartney JE , Wolf EJ , Eisenberg J , Tai MS , Huston JS , Stafford WF , Bookman MA , Houston LL , Weiner LM
Optimization of in-Vivo Tumor Targeting in Scid Mice with Divalent Forms of 741f8 Anti-C-Erbb-2 Single-Chain Fv - Effects of Dose-Escalation and Repeated Iv Administration
Cancer Immunology Immunotherapy. 1995 May;40(5) :299-306
AbstractSingle-chain Fv molecules in monovalent (sFv) and divalent [(sFv')2] forms exhibit highly specific tumor targeting in mice as a result of their small size and rapid systemic clearance. As a consequence, there is a rapid reversal of the sFv blood/tumor gradient, resulting in diminished retention of sFv species in tumors. In this report we investigate two distinct strategies, dose escalation and repetitive intravenous (i.v.) dosing, aiming to increase the absolute selective retention of radiolabeled anti-c-erbB-2 I-125-741F8 (sFv')(2) in c-erbB-2- overexpressing SK-OV-3 tumors in mice with severe combined immunodeficiency (SCID). A dose-escalation strategy was applied to single i.v. injections of I-125-741F8 (sFv')(2). Doses from 50 mu g to 1000 mu g were administered without a significant decrease in tumor targeting or specificity. High doses resulted in large increases in the absolute retention of I-125-741F8 (sFv')(2). For example, raising the administered dose from 50 mu g to 1000 mu g increased the tumor retention 24 h after injection from 0.46 mu g/g to 9.5 mu g/g, and resulted in a net increase of greater than 9 mu g/g. Over the same dose range, the liver retention rose from 0.06 mu g/g to 1 mu g/g, and resulted in a net increase of less than 1 mu g/g. The retention of 9.5 mu g/g in tumor 24 h following the 1000-mu g dose of (sFv')(2) was comparable to that seen 24 h after a 50-mu g dose of I-125-741F8 IgG, indicating that the use of large doses of (sFv')(2) may partially offset their rapid clearance. When two doses were administered by i.v. injection 24 h apart, the specificity of delivery to tumor observed after the first dose was maintained following the second injection. Tumor retention of I-125-741F8 (sFv')2 was 0.32 mu g/g at 24 h and 0.22 mu g/g at 48 h following a single injection of 20 mu g, while 0.04 mu g/ml and 0.03 mu g/ml were retained in blood at the same assay times. After a second 20-mu g injection at the 24-h assay time, tumor retention increased to 0.49 mu g/g, and blood retention was 0.06 mu g/ml, at the 48-h point. These results suggest that multiple high-dose administrations of radiolabeled 741F8 (sFv')(2) map lead to the selective tumor localization of therapeutic radiation doses.
NotesTimes Cited: 8 Article RF806 CANCER IMMUNOL IMMUNOTHER